Programmable therapeutic protein delivery in intestine via amplifier-optimized optogenetic bacteria and LED-equipped electronic capsule

Controllable bacterial therapy in gastrointestinal tract holds therapeutic potential for inflammatory diseases and oncology, but its clinical translation is hindered by insufficient protein expression, inefficient control signal delivery, and lack of adaptability for large-animal models, limiting their practical application. This study proposes an integrated strategy addressing these challenges through two innovations. First, a transcriptional amplifier-optimized optogenetic circuit was engineered in E. coli Nissle 1917, boosting green light-induced protein secretion by up to 41.5 folds compared to dark condition. Second, a wireless LED-emitting electronic capsule was developed, enabling 80 mm deep-tissue wireless signal penetration and smartphone-controlled light delivery. In DSS-induced colitis models, the amplifier-optimized optogenetic strains with 1-h daily light irradiation achieved maximal inflammation alleviation, confirmed by histopathology and disease activity scoring. Pig experiment demonstrated efficient IL-10 accumulation in the rectum after 1-h LED irradiation from the capsule, validating the system's scalability. In conclusion, the dual-optimization strategy combines enhanced optogenetic circuit performance and advanced light irradiation device, enabling programmable and sustained delivery of microbial derived therapeutic proteins. This modular system overcomes limitations of existing approaches, offering adaptable solutions for colorectal disease treatment and gut-axis therapeutics.